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SCIENTIFIC LETTERDD ACE gene polymorphism is associated with increasedcoronary artery endothelial dysfunction: the PREFACE trialH J G H Mulder, P P van Geel, M J Schalij, W H van Gilst, A H Zwinderman,A V G Bruschke. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Heart 2003;89:557–558Endothelial dysfunction is an early event in atherogenesisand is associated with the propensity to cause futurecardiovascular events. The amelioration of endothelialdysfunction has been a research target for some years now,and success has been reported with, for example, the3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reduct-ase inhibitors. Research has also identified the homozygousdeletion (DD) subset of the angiotensin converting enzyme(ACE) insertion(I)/deletion(D) polymorphism to be associ-ated with deteriorated endothelial function. The results, how-ever, are conflicting. In a substudy of the PREFACE(pravastatin-related effects following angioplasty on coronaryendothelium) trial1 we assessed ACE polymorphism, coronaryendothelial function, and the influence of the HMG-CoAreductase inhibitor pravastatin.METHODSPREFACE1 was a randomised, double blinded, placebocontrolled, multicentre study designed to assess the effect ofthree months of treatment with pravastatin (40 mg, oncedaily) on the endothelial function of native and dilated coron-ary arteries in non-smoking, non-hypercholesterolaemicpatients.Coronary endothelium dependent vasomotion at threemonths was assessed by serial, two minute, intracoronaryinfusions of acetylcholine with the final intracoronaryconcentrations estimated to be 10-8, 10-7, and 10-6 M. Hereafterendothelium independent vasomotion was assessed by theinfusion of glyceryl trinitrate at 40 µg per minute for twominutes. Within 15 seconds of each infusion, coronary arteri-ography was performed with a non-ionic contrast mediumand a power injector.Quantitative coronary analysis was performed at the Heart-core angiographic laboratory (Leiden, The Netherlands) in ablinded fashion. Target segments for analysis were the dilatedsegment and an angiographically normal segment. Segmentresponses were calculated as the percentage change in themean segment diameter after infusion relative to the meansegment diameter at baseline.The ACE genotyping was performed according to a modifiedprocedure from Rigat and associates.2Vasomotion measurements were compared between geno-types by mixed model analysis of variance (ANOVA) with theACE genotype and acetylcholine infusion dose as fixed factorsand the patient number as the random factor. The factors ofthe model were expanded with treatment and the interactionfactor treatment/genotype for analysis of these factors. We alsoperformed a pooled analyses of DD versus ID/II as theliterature demonstrates that the DD polymorphism is mostoften associated with deleterious effects, while the ID/II geno-type subsets show similar results.RESULTSFifty two patients (47 men, 5 women) were included in thissubstudy. The groups of patients divided according to ACEgenotype subsets (II, ID, DD) were similar with respect to age,blood pressure, serum lipids, and history of cardiovascularevents. The only discernable difference between the groupswas the number of patients randomised to pravastatin, whichwas significantly higher in the ID group—pravastatin/placebo:II (3/7), ID (21/7), DD (6/8).The luminal parameters of both dilated and normalsegments at baseline and after glyceryl trinitrate infusionwere similar between the genotype subsets. We found that theDD genotype was associated with a significant deterioratedendothelial function as compared to the other genotypes inboth the dilated (p = 0.03) and the normal segment groups(p = 0.01). Pooled analyses of DD subset versus the ID/II sub-set demonstrated increased significance in both the dilated(p = 0.003) and the normal coronary artery segment groups(p = 0.008) (fig 1). When pravastatin treatment was includedin the analyses in the dilated segment group a significanteffect was present (p = 0.04). When the data are pooled asII/ID versus DD an increased significance of the pravastatineffect is observed (p = 0.02).DISCUSSIONPerticone and colleagues used forearm strain gauge plethys-mography to assess endothelial function in patients withnever-treated hypertension.3 They observed an associationbetween the DD genotype and endothelial dysfunction. In thenormotensive control group, however, no association was. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Abbreviations: ACE, angiotensin converting enzyme; HMG-CoA,3-hydroxy-3-methylglutaryl coenzyme A; PREFACE, pravastatin-relatedeffects following angioplasty on coronary endotheliumFigure 1 ACE genotype and change in mean segment diameter fornormal and dilated coronary segments. DD subset versus the ID/IIsubsets demonstrates a significant difference in both the dilated (p =0.003) and the normal coronary artery segment groups (p = 0.008).557www.heartjnl.compresent. This led them to the conclusion that the ACEpolymorphism did not provide the most important componentof endothelial dysfunction. Contrary to these results were thefindings of Butler and colleagues4 who demonstrated anassociation between the insertion/deletion and endothelialfunction in healthy young men.To our knowledge there are no previous reports on the rela-tion between ACE polymorphism and in vivo epicardialcoronary endothelial function. Our results agree with theforearm findings of Butler and colleagues.4 We found anassociation between the DD genotype and deterioratedendothelial function in both normal and dilated coronaryartery segments in patients with few risk factors. Thedominant influence of the DD genotype is demonstrated bythe fact that it is also present in the dilated segments. Theendothelium of these segments has been exposed for only twomonths to factors like hypertension, which exerts its effect inthe long term. To our knowledge there are also no previousreports on the relation between ACE genotype, the use of stat-ins, and coronary endothelial function. We found a significantbeneficial effect of pravastatin in the DD subset of the dilatedsegment group.In summary, this study demonstrates that the DD genotypeis associated with blunted endothelial function of epicardialcoronary arteries. Furthermore an ameliorating effect of prav-astatin in patients with the DD genotype in the dilated coron-ary artery was found. Although the PREFACE trial was notspecifically designed to address the issue of ACE polymor-phism effects on endothelial function, we think the resultsmay be of clinical importance and warrants further research.ACKNOWLEDGEMENTSThe PREFACE trial was supported by Bristol-Myers Squibb Co,Princeton, New Jersey, USA.. . . . . . . . . . . . . . . . . . . . .Authors’ affiliationsH J G H Mulder, M J Schalij, A V G Bruschke, Department ofCardiology, Leiden University Medical Center, Leiden, The NetherlandsP P van Geel, W H van Gilst, Department of Clinical Pharmacology,University Hospital Groningen, Groningen, The NetherlandsA H Zwinderman, Department of Medical Statistics, Leiden University,Leiden, The NetherlandsCorrespondence to: Dr Han JGH Mulder, Department of Cardiology,Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300RC, Leiden, The Netherlands; m.j.schalij@lumc.nlAccepted 20 November 2002REFERENCES1 Mulder HJGH, Schalij MJ, Kauer B, et al. Pravastatin and endotheliumdependent vasomotion after percutaneous transluminal coronaryangioplasty (PTCA): the PREFACE (pravastatin related effects followingangioplasty on coronary endothelium) trial. Heart 2001;86:533–9.2 Schunkert H, Hense HW, Holmer SR, et al. Association between adeletion polymorphism of the angiotensin-converting-enzyme gene andleft ventricular hypertrophy. N Engl J Med 1994;330:1634–8.3 Perticone F, Ceravolo R, Maio R, et al. Angiotensin-converting enzymegene polymorphism is associated with endothelium-dependentvasodilation in never treated hypertensive patients. Hypertension1998;31:900–5.4 Butler R, Morris AD, Burchell B, et al. DD angiotensin-converting enzymegene polymorphism is associated with endothelial dysfunction in normalhumans. Hypertension 1999;33:1164–8.IMAGES IN CARDIOLOGY.............................................................................Prolonged sinus arrest after coronary artery spasmCoronary artery spasm has been proposed as a definitecause of vasospastic angina and as a contributor toother acute cardiac events, including unstable angina,acute myocardial infarction, and sudden cardiac death. It hasalso been demonstrated that silent ischaemia caused bycoronary artery spasm could initiate potentially fatal arrhyth-mias in patients without flow limiting structural coronaryartery lesions. We report a case of prolonged sinus arrest afteran attack of coronary artery spasm.A 50 year old woman presented with recurrent spontaneouschest pain that usually occurred in the morning. She had beendiagnosed as having hypertension two months previouslywithout taking any medication. Resting ECG showed normalsinus rhythm without ST-T wave change (panel A). Treadmillexercise test with Bruce protocol showed no significant STchange with good exercise tolerance. Holter monitoring wasapplied, during which the patient had severe chest painfollowed by syncope at midnight. Holter monitoring duringchest pain showed pronounced ST segment elevation (panelB) followed by bradycardia (panel C). After normalisation ofST segment elevation, prolonged (28 seconds) sinus arrest fol-lowed (panel D), which was the cause of her syncope. Coron-ary angiography showed no significant luminal narrowing.The patient was treated with a calcium channel blocker andnitrates, with a subsequent uneventful clinical course.J-W HaS-Y Chojwha@yumc.yonsei.ac.kr558 Scientific letterwww.heartjnl.com

Prolonged sinus arrest after coronary artery spasm

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Prolonged sinus arrest after coronary artery spasm

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